Activins belong to the transforming growth factor-beta (TGF-β) superfamily and exert a broad range of biological effects on cell proliferation, differentiation, and apoptosis. Activins are homo- or heterodimers of InhibinβA, InhibinβB, InhibinβC and InhibinβE, different combinations of which create the various members of the activin protein group. For example, Activin A is a homodimer of InhibinβA and Activin B is a homodimer of InhibinβB, whereas Activin AB is a heterodimer of InhibinβA and InhibinβB and Activin AC is a heterodimer of InhibinβA and InhibinβC (Tsuchida, K. et al., Cell Commun Signal 7:15 (2009)).
Activin A binds to and activates receptor complexes on the surface of cells known as Activin Type II receptors (Type IIA and Type IIB, also known as ActRIIA and ActRIIB, respectively). The activation of these receptors leads to the phosphorylation of an Activin Type I receptor (e.g., Alk4 or 7), which in turn leads to the phosphorylation of SMAD 2 and 3 proteins, the formation of SMAD complexes (with SMAD4), and the translocation of the SMAD complex to the cell nucleus, where SMAD2 and SMAD3 function to regulate transcription of various genes (Sozzani, S, and Musso, T., Blood 117(19):5013-5015 (2011)).
Numerous other ligands bind to and activate ActRIIB, including GDF8 (myostatin), Activin B, Activin AB, Inhibin A, Inhibin B, GDF3, GDF11, Nodal, BMP2, BMP4, BMP7, BMP9, and BMP10. Blocking the interactions of ActRIIB with its ligands can lead to beneficial physiological effects. For example, GDF8 plays a central role in the development and maintenance of skeletal muscle, acting as a negative regulator of muscle mass (McPherron A C et al. (1997). Nature 387(6628):83-90). Administration of ActRIIB-Fc (i.e., the extracellular portion of the Type IIB receptor, ActRIIB, stabilized by fusion to an IgG Fc domain) leads to significant increases in skeletal muscle mass and improves muscle weight and measurements of muscle strength in mice (Lee S J, et al. (2005) Proc Natl Acad Sci USA 102(50):18117-18122). The efficacy of ActRIIB-Fc is attenuated but not eliminated in Mstn (myostatin) null mice, demonstrating that other ActRIIB ligand(s) in addition to myostatin can function as negative regulators of muscle growth. Thus, a need exists for additional inhibitors of ActRIIB signaling that can provide clinical benefits.